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Novel Secondary Metabolites from Endophytic Marine-Derived Fungi

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Novel Secondary Metabolites from Endophytic Marine-Derived Fungi Novel Secondary Metabolites from Endophytic Marine-derived Fungi Dissertation zur Erlangung des Doktorgrades (Dr. rer. nat.) der Mathematisch-Naturwissenschaftlichen Fakultät der Rheinischen Friedrich-Wilhelms-Universität Bonn vorgelegt von Celso Almeida aus Lissabon, Portugal Bonn 2011 2 Angefertigt mit Genehmigung der Mathematisch-Naturwissenschaftlichen Fakultät der Rheinischen Friedrich-Wilhelms-Universität Bonn 1. Gutachterin : Prof. Dr. G. M. König 2. Gutachterin : Prof. Dr. E. Kostenis Tag der Promotion : 15. Februar 2011 Erscheinungsjahr : 2011 3 Vorveröffentlichungen der Dissertation/In Advance Publications of the Dissertation Teilergebnisse aus dieser Arbeit wurden mit Genehmigung der Mathematisch- Naturwissenschaftlichen Fakultät, vertreten durch die Mentorin/Betreuerin der Arbeit, in folgenden Beiträgen vorab veröffentlicht: Parts of this study have been published in advance by permission of the Mathematisch- Naturwissenschaftlichen Fakultät, represented by the supervisor of this study: Publikationen / Research Papers Almeida C., Eguereva E., Kehraus S., Siering C. and König G.M., Hydroxylated Sclerosporin Derivatives from the Marine-derived Fungus Cadophora malorum, J. Nat. Prod., 2010, 73 (3), pp 476–478. Almeida C., Elsaedi S., Kehraus S. and König G. M., Novel Bisabolane Sesquiterpenes from the Marine-derived Fungus Verticillium tenerum, Nat. Prod. Commun. 2010, 5(4), 507- 10. Almeida C., Part N., Kehraus S. and König G. M., Stachylines A – D from the Sponge-derived Fungus Stachylidium sp. (accepted by Journal of Natural Products). Almeida C., Kehraus S., Prudêncio M. and König G. M., Marilones A – J, Unusual Phthalides from the Sponge-derived Fungus Stachylidium sp. (submitted to European Journal of Organic Chemistry). Almeida C., Kehraus S., Dimas K., Gütschow M. and König G. M., Marilines A – D, Novel Phthalimidines from the Sponge-derived Fungus Stachylidium sp. (In preparation) Almeida C., Kehraus S. and König G. M., Novel Furyl Derivative from the Sponge-derived Fungus Stachylidium sp. (In preparation). Almeida C., Kehraus S. and König G. M. Novel bioactive peptides from the Sponge-derived Fungus Stachylidium sp. (In preparation). 4 Tagungsbeiträge/Research Presentations Almeida C., Kehraus S., König G. M., Hydroxylated derivatives of a rare cadinane-type sesquiterpene isolated from a cytotoxic Wardomyces inflatus extract. Poster presented at the 7th Natural Products Joint Meeting of AFERP, ASP, GA, PSE & SIF, August 3-8, 2008, Athens, Greece. Almeida C., Kehraus S., König G. M., Hydroxylated derivatives of a rare cadinane-type sesquiterpene isolated from a cytotoxic Wardomyces inflatus extract. Poster presented at the Joint Meeting of the Deutsche Pharmazeutische Gesellschaft (DPhG), October 8-11, 2008, Bonn, Germany. Almeida C., König G. M., Novel secondary metabolites from the sponge-derived fungus Stachylidium sp.; tracking bacterial endosymbionts. Oral presentation at the 50th Annual Meeting of the American Society of Pharmacognosy, June 27-July 1, 2009, Honolulu, Hawaii. Almeida C., König G. M., Novel Secondary Metabolites from the Sponge-Derived Fungus Stachylidium sp.; Tracking Bacterial Endosymbionts. Poster presented at the 6th European Conference on Marine Natural Products, July 19 - 23, 2009, Porto, Portugal. Almeida C., Kehraus S., Dimas K., and König G. M., Marilines A – D, Novel Phthalimidines from the Sponge-derived Fungus Stachylidium sp. Poster presented at the International Conference New Biotrends in Green Chemistry, December 1-2, 2010, Dortmund, Germany. 5 To my mother, Marilia, and father, Benjamim 6 Acknowledgements I wish to express my sincere gratitude and admiration to my supervisor Prof. Dr. G. M. König for the expert guidance, encouragement and kind support during the course of this project. I would like to thank her for providing excellent scientific advice, working facilities, for letting me express my creativity, and especially for understanding and guidance in unexpected personal difficulties that arose during the research. I have nothing else than to be proud and consider to be a truly privilege to have performed a PhD under the orientation of Prof. Dr. G. M. König. Special thanks go to Prof. Dr. E. Kostenis for officiating as second referee. Many specific tasks involved in this study were performed in cooperation with other members of the Institute for Pharmaceutical Biology, Uni Bonn. For this work cordial thanks go to: Dr. Stefan Kehraus for indispensable help concerning the implementation and interpretation of special NMR experiments, for proofreading manuscripts and thesis, and for providing friendly, professional laboratory support during all phases of this study. I would also like to express my extreme admiration for the NMR interpretation skills of Dr. Kehraus. Ekaterina Eguereva for introducing me to the work with marine-derived fungi. Also thanks for recording all LC-MS spectra and friendly talks during the research. Edith Neu for conducting agar diffusion assays and for being such a friendly person. Natalja Part, for her outstanding lab work and for being a good friend. E. Gassen for friendly assistance and for resolving all administrative questions. I would like to thank all members of the Institute for Pharmaceutical Biology, University of Bonn, present or past for cooperation and friendship, with special regards to Hendrik Greve and Ana Kralj for the great help in the first year in the lab. Extra-special thanks go to Sanem Insu Tezkan, words cannot describe her existance. As for Rita Roque, Rui Branco and Paulo Figueiredo, thank you for making the days in Germany so special, I met you here but the friendship will be for life. Also for Maria Laura Vinuela which will be in my heart for the rest of my life. Another thanks goes to Ricardo Baptista Lopes, long time friend that is allways there when i return to Portugal. A final thankfull word for “pre-PhD“ personalities, namely Dr. Rob Verpoorte (Leiden University, The Netherlands) for all the knowledge given during my Masters, and Dr. Artur Silva 7 (Aveiro University, Portugal) for teaching exquisidly the basics of NMR spectroscopy to a biologist, which was essencial for this PhD work. Financial support for this project was provided by FCT (Fundação para a Ciencia e Tecnologia, Portugal) and is gratefully acknowledged. International scientific cooperation acknowledgements. I thank the efforts of Dr. K. Dimas (Biomedical Research Foundation of Academy of Athens, Greece) for the cytotoxicity assays, Prof. Dr. M. Gütschow (Institute for Pharmaceutical Chemistry, University of Bonn, Germany) for performing the panel of proteases inhibition assays, Dr. L. Meijer (Protein Phosphorylation & Disease, CNRS, Roscoff, France) for performing the protein kinases assays and Dr. C. Pannecouque (Rega Institute for Medical Research, Leuven, Belgium) for performing the HIV-1 and HIV-2 antiviral assays; I also kindly thank Dr. M. Prudêncio (Malaria Unit, Institute for Molecular Medicine, University of Lisbon, Portugal) for performing the antiplasmodial activity assays, Indra Bergval (KIT Biomedical Research, Royal Tropical Institute, Amsterdam, Netherlands) for performing the M. tuberculosis activity assays, Dr. Marc Diederich (LBMCC, Luxembourg) for performing the NF-kB activity assays, Dr. Steinar Paulsen (University of Tromsø, MabCent, Tromsø, Norway) for performing the anti-diabetic activity assays and Dr. K. Shimokawa (Department of Chemistry, Nagoya University, Japan) for performing the 3T3-L1 murine adipocytes assay; the Ki determinations and antagonist functional data that was generously provided by the National Institute of Mental Health's Psychoactive Drug Screening Program, Contract # HHSN-271-2008-00025-C (NIMH PDSP). The NIMH PDSP is directed by Bryan L. Roth MD, PhD at the University of North Carolina at Chapel Hill and Project Officer Jamie Driscol at NIMH, Bethesda MD, USA; I kindly thank also the remaining antiviral tests performed by the U.S. National Institute of Health which were supported by contracts NO1-A1-30048 (Institute for Antiviral Research, IAR) and NO1-AI-15435 (IAR) from Virology Branch, National Institute of Allergic and Infectious Diseases, NIAID; also a thankful word for Dr. M. Engeser and Dr. B. Sondag (Kekulé-Institute for Organic Chemistry and Biochemistry, University of Bonn) for the High Resolution Mass Spectrometry efforts. Synthetic reference compounds for CD spectra comparison with verticonols A/B were kindly provided by Dr. Kenji Mori, Emeritus Professor from the University of Tokyo, Japan; special thanks to Carsten Siering (Kekulé Institute for Organic and Inorganic Chemistry, University of Bonn) for CD spectral measurements and invaluable discussions. 8 Table of contents Page 1. Introduction …………………………….…………………………………….….1 2. Scope of the present study …………………………………….………...……..14 3. General methodology ……………………………………………….…………15 4. Marilines A – D, novel phthalimidines from the sponge-derived fungus Stachylidium sp. ......................................................................................18 5. Marilones A – J, unusual phthalides from the sponge-derived fungus Stachylidium sp. ......................................................................................36 6. Stachylines A – D from the sponge-derived fungus Stachylidium sp. ................56 7. Novel furyl derivative from the sponge-derived fungus Stachylidium sp. .......70 8. Endolides A – J, N-methylated peptides from the sponge-derived fungus Stachylidium sp. ......................................................................................75
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